PROJECT SUMMARY Candidate: Dr. Matthew Semler, MD, MSCI is an Assistant Professor at Vanderbilt University Medical Center. Dr. Semler has a strong background in critical care clinical trials gained through both his formal training in clinical research and his work conducting prior comparative effectiveness trials in fluid management and respiratory support. His long-term career plan is to become a physician scientist recognized as the national leader in the integration of pragmatic comparative effectiveness trials into the delivery of critical care. To achieve this, his immediate goals are to learn the clinical informatics methods needed to embed clinical trials within the electronic health record, advance his methodologic expertise in novel trial designs, and master the advanced modeling techniques required to predict the effect of therapy for individual patients. Research Project: Each year 2-3 million critically ill adults receive invasive mechanical ventilation, with an associated in-hospital mortality of 25-35%. Mechanical ventilation of critically ill adults universally involves titration of the fraction of inspired oxygen (FiO2) to maintain arterial oxygen saturation (SpO2), and yet the optimal SpO2 target remains unknown. Both hyperoxia and hypoxia may influence organ function, and improved understanding of the effects of SpO2 target during mechanical ventilation on clinical outcomes of critical illness is urgently needed. The Specific Aims of the proposed research are: Aim 1) Conduct the Pragmatic Investigation of optimaL Oxygen Targets (PILOT) trial, a 2,250-patient cluster-crossover trial testing the hypothesis that use of a lower SpO2 target (90%) for mechanically ventilated ICU patients will result in more days alive and free of invasive mechanical ventilation than use of an intermediate SpO2 target (94%) or a higher SpO2 target (98%); and Aim 2) Develop a statistical model predicting the effect of SpO2 target on clinical outcomes for individual patients, using data from the PILOT trial. Career Development: Dr. Semler?s career development plan integrates formal coursework with personalized training with his mentors and collaborators to: 1) strengthen his methodologic foundation in the conduct of pragmatic comparative effectiveness trials; 2) develop expertise in novel clinical trial designs; 3) master advanced statistical modeling techniques for cluster-level data and predicting the effect of therapy for individual patients within a trial, and 4) bolstering his skills as a leader of multi-disciplinary research teams. Environment: VUMC is the ideal environment to foster Dr. Semler?s development into a national leader in pragmatic comparative effectiveness trials within critical care. The environment includes an unparalleled team of NIH-funded mentors and collaborators, an internationally-recognized bioinformatics infrastructure, and the new Learning Healthcare System component of Vanderbilt?s Clinical and Translational Science Award (CTSA), funded to develop the novel methods for integrating clinical research into clinical care that form the basis for the proposed research project and career development plan.